The role of necroptosis-regulated mitochondrial DNA release in the pathogeneisis of COPD
| Project/Area Number |
18K08159
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 53030:Respiratory medicine-related
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| Research Institution | Nihon University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
権 寧博 日本大学, 医学部, 教授 (80339316)
丸岡 秀一郎 日本大学, 医学部, 准教授 (80599358)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
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| Keywords | COPD / タバコ煙 / ネクロプト－シス / ミトコンドリア / ミトコンドリアDNA / 気腫性変化 / 気道炎症 / ネクロプトーシス / 鉄代謝 |
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| Outline of Final Research Achievements |
The pathogenesis of COPD has not yet been fully elucidated. Previously, we demonstrated that cigarette smoke (CS) causes mitochondrial dysfunction in the lungs and subsequently induces necroptosis. Accumulating evidence indicates that mitochondrial dysfunction causes the extracellular leakage of mitochondrial DNA (mtDNA). However, the molecular mechanisms underlying CS-induced extracellular leakage of mtDNA are not fully understood. In this study, we demonstrated that CS induces mtDNA release to the extracellular space in pulmonary epithelial cells. The necroptosis inhibitor, necrostatin-1, reduced CS induced extracellular mtDNA release, but not from mitochondria to the cytosol. Notably, the transfection of mtDNA into pulmonary epithelial cells reduced IL-6 production. These findings suggest that necroptosis regulates CS-induced extracellular mtDNA release in pulmonary epithelial cells, which may impact airway inflammation in COPD by downregulating IL-6 production.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究は、アポトーシス研究で明らかにできなかったCOPDにおける気腫性変化と気道炎症の関係をネクロプトーシスに着目することで解明し、診断と治療応用の基盤を確立することを目的とした。本研究で、タバコ煙によるミトコンドリア損傷と気道炎症を結ぶセカンドメッセンジャーとしてミトコンドリア由来DAMPsであるミトコンドリアDNAがCOPDの病態生理に関与することが明らかとなった。本メカニズムにネクロプト－シスが重要な役割を果たしており、DAMPs放出の少ないアポトーシス研究にはなかった側面であり、学術的独自性がある。本メカニズムの制御により新たなCOPDの診断、治療法の開発につながる可能性がある。
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Report
(4 results)
Research Products
(2 results)
